Drug/drug delivery systems for the prevention and treatment of vascular disease

ABSTRACT

A drug and drug delivery system may be utilized in the treatment of vascular disease. A local delivery system is coated with rapamycin or other suitable drug, agent or compound and delivered intraluminally for the treatment and prevention of neointimal hyperplasia following percutaneous transluminal coronary angiography. The local delivery of the drugs or agents provides for increased effectiveness and lower systemic toxicity.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part application of U.S.application Ser. No. 09/850,293 filed on May 7, 2001 which is acontinuation-in-part application of U.S. application Ser. No.09/575,480, filed on May 19, 2000 which claims the benefit of U.S.Provisional Application No. 60/204,417, filed May 12, 2000 and claimsthe benefit of U.S. Provisional Application No. 60/262,614, filed Jan.18, 2001, U.S. Provisional Application No. 60/262,461, filed Jan. 18,2001, U.S. Provisional Application No. 60/263,806, filed Jan. 24, 2001and U.S. Provisional Application No. 60/263,979, filed Jan. 25, 2001.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to drugs and drug delivery systemsfor the prevention and treatment of vascular disease, and moreparticularly to drugs and drug delivery systems for the prevention andtreatment of neointimal hyperplasia.

[0004] 2. Discussion of the Related Art

[0005] Many individuals suffer from circulatory disease caused by aprogressive blockage of the blood vessels that perfuse the heart andother major organs with nutrients. More severe blockage of blood vesselsin such individuals often leads to hypertension, ischemic injury,stroke, or myocardial infarction. Atherosclerotic lesions, which limitor obstruct coronary blood flow, are the major cause of ischemic heartdisease. Percutaneous transluminal coronary angioplasty is a medicalprocedure whose purpose is to increase blood flow through an artery.Percutaneous transluminal coronary angioplasty is the predominanttreatment for coronary vessel stenosis. The increasing use of thisprocedure is attributable to its relatively high success rate and itsminimal invasiveness compared with coronary bypass surgery. A limitationassociated with percutaneous transluminal coronary angioplasty is theabrupt closure of the vessel which may occur immediately after theprocedure and restenosis which occurs gradually following the procedure.Additionally, restenosis is a chronic problem in patients who haveundergone saphenous vein bypass grafting. The mechanism of acuteocclusion appears to involve several factors and may result fromvascular recoil with resultant closure of the artery and/or depositionof blood platelets and fibrin along the damaged length of the newlyopened blood vessel.

[0006] Restenosis after percutaneous transluminal coronary angioplastyis a more gradual process initiated by vascular injury. Multipleprocesses, including thrombosis, inflammation, growth factor andcytokine release, cell proliferation, cell migration and extracellularmatrix synthesis each contribute to the restenotic process.

[0007] While the exact mechanism of restenosis is not completelyunderstood, the general aspects of the restenosis process have beenidentified. In the normal arterial wall, smooth muscle cells proliferateat a low rate, approximately less than 0.1 percent per day. Smoothmuscle cells in the vessel walls exist in a contractile phenotypecharacterized by eighty to ninety percent of the cell cytoplasmic volumeoccupied with the contractile apparatus. Endoplasmic reticulum, Golgi,and free ribosomes are few and are located in the perinuclear region.Extracellular matrix surrounds the smooth muscle cells and is rich inheparin-like glycosylaminoglycans which are believed to be responsiblefor maintaining smooth muscle cells in the contractile phenotypic state(Campbell and Campbell, 1985).

[0008] Upon pressure expansion of an intracoronary balloon catheterduring angioplasty, smooth muscle cells within the vessel wall becomeinjured, initiating a thrombotic and inflammatory response. Cell derivedgrowth factors such as platelet derived growth factor, fibroblast growthfactor, epidermal growth factor, thrombin, etc., released fromplatelets, invading macrophages and/or leukocytes, or directly from thesmooth muscle cells provoke proliferative and migratory responses inmedial smooth muscle cells. These cells undergo a change from thecontractile phenotype to a synthetic phenotype characterized by only afew contractile filament bundles, extensive rough endoplasmic reticulum,Golgi and free ribosomes. Proliferation/migration usually begins withinone to two days post-injury and peaks several days thereafter (Campbelland Campbell, 1987; Clowes and Schwartz, 1985).

[0009] Daughter cells migrate to the intimal layer of arterial smoothmuscle and continue to proliferate and secrete significant amounts ofextracellular matrix proteins. Proliferation, migration andextracellular matrix synthesis continue until the damaged endotheliallayer is repaired at which time proliferation slows within the intima,usually within seven to fourteen days post-injury. The newly formedtissue is called neointima. The further vascular narrowing that occursover the next three to six months is due primarily to negative orconstrictive remodeling.

[0010] Simultaneous with local proliferation and migration, inflammatorycells invade the site of vascular injury. Within three to seven dayspost-injury, inflammatory cells have migrated to the deeper layers ofthe vessel wall. In animal models employing either balloon injury orstent implantation, inflammatory cells may persist at the site ofvascular injury for at least thirty days (Tanaka et al., 1993; Edelmanet al., 1998). Inflammatory cells therefore are present and maycontribute to both the acute and chronic phases of restenosis.

[0011] Numerous agents have been examined for presumedanti-proliferative actions in restenosis and have shown some activity inexperimental animal models. Some of the agents which have been shown tosuccessfully reduce the extent of intimal hyperplasia in animal modelsinclude: heparin and heparin fragments (Clowes, A. W. and Karnovsky M.,Nature 265: 25-26, 1977; Guyton, J. R. et al., Circ. Res., 46: 625-634,1980; Clowes, A. W. and Clowes, M. M., Lab. Invest. 52: 611-616, 1985;Clowes, A. W. and Clowes, M. M., Circ. Res. 58: 839-845, 1986; Majeskyet al., Circ. Res. 61: 296-300, 1987; Snow et al., Am. J. Pathol. 137:313-330, 1990; Okada, T. et al., Neurosurgery 25: 92-98, 1989),colchicine (Currier, J. W. et al., Circ. 80: 11-66, 1989), taxol(Sollot, S. J. et al., J. Clin. Invest. 95: 1869-1876, 1995),angiotensin converting enzyme (ACE) inhibitors (Powell, J. S. et al.,Science, 245: 186-188, 1989), angiopeptin (Lundergan, C. F. et al. Am.J. Cardiol. 17(Suppl. B):132B-136B, 1991), cyclosporin A (Jonasson, L.et al., Proc. Natl., Acad. Sci., 85: 2303, 1988), goat-anti-rabbit PDGFantibody (Ferns, G. A. A., et al., Science 253: 1129-1132, 1991),terbinafine (Nemecek, G. M. et al., J. Pharmacol. Exp. Thera. 248:1167-1174, 1989), trapidil (Liu, M. W. et al., Circ. 81: 1089-1093,1990), tranilast (Fukuyama, J. et al., Eur. J. Pharmacol. 318: 327-332,1996), interferon-gamma (Hansson, G. K. and Holm, J., Circ. 84:1266-1272, 1991), rapamycin (Marx, S. O. et al., Circ. Res. 76: 412-417,1995), corticosteroids (Colburn, M. D. et al., J. Vasc. Surg. 15:510-518, 1992), see also Berk, B. C. et al., J. Am. Coll. Cardiol. 17:111B-117B, 1991), ionizing radiation (Weinberger, J. etal., Int. J. Rad.Onc. Biol. Phys. 36: 767-775, 1996), fusion toxins (Farb, A. et al.,Circ. Res. 80: 542-550, 1997) antisense oligonucleotides (Simons, M. etal., Nature 359: 67-70, 1992) and gene vectors (Chang, M. W. et al., J.Clin. Invest. 96: 2260-2268, 1995). Anti-proliferative effects on smoothmuscle cells in vitro have been demonstrated for many of these agents,including heparin and heparin conjugates, taxol, tranilast, colchicine,ACE inhibitors, fusion toxins, antisense oligonucleotides, rapamycin andionizing radiation. Thus, agents with diverse mechanisms of smoothmuscle cell inhibition may have therapeutic utility in reducing intimalhyperplasia.

[0012] However, in contrast to animal models, attempts in humanangioplasty patients to prevent restenosis by systemic pharmacologicmeans have thus far been unsuccessful. Neither aspirin-dipyridamole,ticlopidine, anti-coagulant therapy (acute heparin, chronic warfarin,hirudin or hirulog), thromboxane receptor antagonism nor steroids havebeen effective in preventing restenosis, although platelet inhibitorshave been effective in preventing acute reocclusion after angioplasty(Mak and Topol, 1997; Lang et al., 1991; Popma et al., 1991). Theplatelet GP IIb/IIIa receptor, antagonist, Reopro is still under studybut has not shown promising results for the reduction in restenosisfollowing angioplasty and stenting. Other agents, which have also beenunsuccessful in the prevention of restenosis, include the calciumchannel antagonists, prostacyclin mimetics, angiotensin convertingenzyme inhibitors, serotonin receptor antagonists, andanti-proliferative agents. These agents must be given systemically,however, and attainment of a therapeutically effective dose may not bepossible; anti-proliferative (or anti-restenosis) concentrations mayexceed the known toxic concentrations of these agents so that levelssufficient to produce smooth muscle inhibition may not be reached (Makand Topol, 1997; Lang et al., 1991; Popma et al., 1991).

[0013] Additional clinical trials in which the effectiveness forpreventing restenosis utilizing dietary fish oil supplements orcholesterol lowering agents has been examined showing either conflictingor negative results so that no pharmacological agents are as yetclinically available to prevent post-angioplasty restenosis (Mak andTopol, 1997; Franklin and Faxon, 1993: Serruys, P. W. et al., 1993).Recent observations suggest that the antilipid/antioxidant agent,probucol may be useful in preventing restenosis but this work requiresconfirmation (Tardif et al., 1997; Yokoi, et al., 1997). Probucol ispresently not approved for use in the United States and a thirty-daypretreatment period would preclude its use in emergency angioplasty.Additionally, the application of ionizing radiation has shownsignificant promise in reducing or preventing restenosis afterangioplasty in patients with stents (Teirstein et al., 1997). Currently,however, the most effective treatments for restenosis are repeatangioplasty, atherectomy or coronary artery bypass grafting, because notherapeutic agents currently have Food and Drug Administration approvalfor use for the prevention of post-angioplasty restenosis.

[0014] Unlike systemic pharmacologic therapy, stents have proveneffective in significantly reducing restenosis. Typically, stents areballoon-expandable slotted metal tubes (usually, but not limited to,stainless steel), which, when expanded within the lumen of anangioplastied coronary artery, provide structural support through rigidscaffolding to the arterial wall. This support is helpful in maintainingvessel lumen patency. In two randomized clinical trials, stentsincreased angiographic success after percutaneous transluminal coronaryangioplasty, by increasing minimal lumen diameter and reducing, but noteliminating, the incidence of restenosis at six months (Serruys et al.,1994; Fischman et al., 1994).

[0015] Additionally, the heparin coating of stents appears to have theadded benefit of producing a reduction in sub-acute thrombosis afterstent implantation (Serruys et al., 1996). Thus, sustained mechanicalexpansion of a stenosed coronary artery with a stent has been shown toprovide some measure of restenosis prevention, and the coating of stentswith heparin has demonstrated both the feasibility and the clinicalusefulness of delivering drugs locally, at the site of injured tissue.

[0016] Accordingly, there exists a need for effective drugs and drugdelivery systems for the effective prevention and treatment ofneointimal thickening that occurs after percutaneous transluminalcoronary angioplasty and stent implantation.

SUMMARY OF THE INVENTION

[0017] The drugs and drug delivery systems of the present inventionprovide a means for overcoming the difficulties associated with themethods and devices currently in use as briefly described above.

[0018] In accordance with one aspect, the present invention is directedto a method for the prevention of constrictive remodeling. The methodcomprises the controlled delivery, by release from an intraluminalmedical device, of a compound in therapeutic dosage amounts.

[0019] In accordance with another aspect, the present invention isdirected to a drug delivery device. The drug delivery device comprisesan intraluminal medical device and a therapeutic dosage of an agentreleasably affixed to the intraluminal medical device for the treatmentof constrictive vascular remodeling.

[0020] The drugs and drug delivery systems of the present inventionutilize a stent or graft in combination with rapamycin or otherdrugs/agents/compounds to prevent and treat neointimal hyperplasia, i.e.restenosis, following percutaneous transluminal coronary angioplasty andstent implantation. It has been determined that rapamycin functions toinhibit smooth muscle cell proliferation through a number of mechanisms.It has also been determined that rapamycin eluting stent coatingsproduce superior effects in humans, when compared to animals, withrespect to the magnitude and duration of the reduction in neointimalhyperplasia. Rapamycin administration from a local delivery platformalso produces an anti-inflammatory effect in the vessel wall that isdistinct from and complimentary to its smooth muscle cellanti-proliferative effect. In addition, it has also been demonstratedthat rapamycin inhibits constrictive vascular remodeling in humans.

[0021] Other drugs, agents or compounds which mimic certain actions ofrapamycin may also be utilized in combination with local deliverysystems or platforms.

[0022] The local administration of drugs, agents or compounds to stentedvessels have the additional therapeutic benefit of higher tissueconcentration than that which would be achievable through the systemicadministration of the same drugs, agents or compounds. Other benefitsinclude reduced systemic toxicity, single treatment, and ease ofadministration. An additional benefit of a local delivery device anddrug, agent or compound therapy may be to reduce the dose of thetherapeutic drugs, agents or compounds and thus limit their toxicity,while still achieving a reduction in restenosis.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The foregoing and other features and advantages of the inventionwill be apparent from the following, more particular description ofpreferred embodiments of the invention, as illustrated in theaccompanying drawings.

[0024]FIG. 1 is a chart indicating the effectiveness of rapamycin as ananti-inflammatory relative to other anti-inflammatories.

[0025]FIG. 2 is a view along the length of a stent (ends not shown)prior to expansion showing the exterior surface of the stent and thecharacteristic banding pattern.

[0026]FIG. 3 is a perspective view of the stent of FIG. 1 havingreservoirs in accordance with the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] As stated above, the proliferation of vascular smooth musclecells in response to mitogenic stimuli that are released during balloonangioplasty and stent implantation is the primary cause of neointimalhyperplasia. Excessive neointimal hyperplasia can often lead toimpairment of blood flow, cardiac ischemia and the need for a repeatintervention in selected patients in high risk treatment groups. Yetrepeat revascularization incurs risk of patient morbidity and mortalitywhile adding significantly to the cost of health care. Given thewidespread use of stents in interventional practice, there is a clearneed for safe and effective inhibitors of neointimal hyperplasia.

[0028] Rapamycin is a macroyclic triene antibiotic produced bystreptomyces hygroscopicus as disclosed in U.S. Pat. No. 3,929,992. Ithas been found that rapamycin inhibits the proliferation of vascularsmooth muscle cells in vivo. Accordingly, rapamycin may be utilized intreating intimal smooth muscle cell hyperplasia, restenosis and vascularocclusion in a mammal, particularly following either biologically ormechanically mediated vascular injury, or under conditions that wouldpredispose a mammal to suffering such a vascular injury. Rapamycinfunctions to inhibit smooth muscle cell proliferation and does notinterfere with the re-endothelialization of the vessel walls.

[0029] Rapamycin functions to inhibit smooth muscle cell proliferationthrough a number of mechanisms. In addition, rapamycin reduces the othereffects caused by vascular injury, for example, inflammation. Theoperation and various functions of rapamycin are described in detailbelow. Rapamycin as used throughout this application shall includerapamycin, rapamycin analogs, derivatives and congeners that bind FKBP12and possess the same pharmacologic properties as rapamycin.

[0030] Rapamycin reduces vascular hyperplasia by antagonizing smoothmuscle proliferation in response to mitogenic signals that are releasedduring angioplasty. Inhibition of growth factor and cytokine mediatedsmooth muscle proliferation at the late G1 phase of the cell cycle isbelieved to be the dominant mechanism of action of rapamycin. However,rapamycin is also known to prevent T-cell proliferation anddifferentiation when administered systemically. This is the basis forits immunosuppresive activity and its ability to prevent graftrejection.

[0031] The molecular events that are responsible for the actions ofrapamycin, a known anti-proliferative, which acts to reduce themagnitude and duration of neointimal hyperplasia, are still beingelucidated. It is known, however, that rapamycin enters cells and bindsto a high-affinity cytosolic protein called FKBP12. The complex ofrapamycin and FKPB12 in turn binds to and inhibits a phosphoinositide(PI)-3 kinase called the “mammalian Target of Rapamycin” or TOR. TOR isa protein kinase that plays a key role in mediating the downstreamsignaling events associated with mitogenic growth factors and cytokinesin smooth muscle cells and T lymphocytes. These events includephosphorylation of p27, phosphorylation of p70 s6 kinase andphosphorylation of 4BP-1, an important regulator of protein translation.

[0032] It is recognized that rapamycin reduces restenosis by inhibitingneointimal hyperplasia. However, there is evidence that rapamycin mayalso inhibit the other major component of restenosis, namely, negativeremodeling. Remodeling is a process whose mechanism is not clearlyunderstood but which results in shrinkage of the external elastic laminaand reduction in lumenal area over time, generally a period ofapproximately three to six months in humans.

[0033] Negative or constrictive vascular remodeling may be quantifiedangiographically as the percent diameter stenosis at the lesion sitewhere there is no stent to obstruct the process. If late lumen loss isabolished in-lesion, it may be inferred that negative remodeling hasbeen inhibited. Another method of determining the degree of remodelinginvolves measuring in-lesion external elastic lamina area usingintravascular ultrasound (IVUS). Intravascular ultrasound is a techniquethat can image the external elastic lamina as well as the vascularlumen. Changes in the external elastic lamina proximal and distal to thestent from the post-procedural timepoint to four-month and twelve-monthfollow-ups are reflective of remodeling changes.

[0034] Evidence that rapamycin exerts an effect on remodeling comes fromhuman implant studies with rapamycin coated stents showing a very lowdegree of restenosis in-lesion as well as in-stent. In-lesion parametersare usually measured approximately five millimeters on either side ofthe stent i.e. proximal and distal. Since the stent is not present tocontrol remodeling in these zones which are still affected by balloonexpansion, it may be inferred that rapamycin is preventing vascularremodeling.

[0035] The data in Table 1 below illustrate that in-lesion percentdiameter stenosis remains low in the rapamycin treated groups, even attwelve months. Accordingly, these results support the hypothesis thatrapamycin reduces remodeling. TABLE 1.0 Angiographic In-Lesion PercentDiameter Stenosis (%, mean ± SD and “n=”) In Patients Who Received aRapamycin-Coated Stent Coating Post 4-6 month 12 month Group PlacementFollow Up Follow Up Brazil 10.6 ± 5.7 13.6 ± 8.6 22.3 ± 7.2 (30) (30)(15) Netherlands 14.7 ± 8.8 22.4 ± 6.4 —

[0036] Additional evidence supporting a reduction in negative remodelingwith rapamycin comes from intravascular ultrasound data that wasobtained from a first-in-man clinical program as illustrated in Table 2below. TABLE 2.0 Matched IVUS data in Patients Who Received aRapamycin-Coated Stent 4-Month 12-Month Follow-Up Follow-Up IVUSParameter Post (n=) (n=) (n=) Mean proximal vessel area 16.53 ± 3.5316.31 ± 4.36 13.96 ± 2.26 (mm²) (27) (28) (13) Mean distal vessel area13.12 ± 3.68 13.53 ± 4.17 12.49 ± 3.25 (mm²) (26) (26) (14)

[0037] The data illustrated that there is minimal loss of vessel areaproximally or distally which indicates that inhibition of negativeremodeling has occurred in vessels treated with rapamycin-coated stents.

[0038] Other than the stent itself, there have been no effectivesolutions to the problem of vascular remodeling. Accordingly, rapamycinmay represent a biological approach to controlling the vascularremodeling phenomenon.

[0039] It may be hypothesized that rapamycin acts to reduce negativeremodeling in several ways. By specifically blocking the proliferationof fibroblasts in the vascular wall in response to injury, rapamycin mayreduce the formation of vascular scar tissue. Rapamycin may also affectthe translation of key proteins involved in collagen formation ormetabolism.

[0040] Rapamycin used in this context includes rapamycin and allanalogs, derivatives and congeners that bind FKBP12 and possess the samepharmacologic properties as rapamycin.

[0041] In a preferred embodiment, the rapamycin is delivered by a localdelivery device to control negative remodeling of an arterial segmentafter balloon angioplasty as a means of reducing or preventingrestenosis. While any delivery device may be utilized, it is preferredthat the delivery device comprises a stent that includes a coating orsheath which elutes or releases rapamycin. The delivery system for sucha device may comprise a local infusion catheter that delivers rapamycinat a rate controlled by the administrator.

[0042] Rapamycin may also be delivered systemically using an oral dosageform or a chronic injectible depot form or a patch to deliver rapamycinfor a period ranging from about seven to forty-five days to achievevascular tissue levels that are sufficient to inhibit negativeremodeling. Such treatment is to be used to reduce or prevent restenosiswhen administered several days prior to elective angioplasty with orwithout a stent.

[0043] Data generated in porcine and rabbit models show that the releaseof rapamycin into the vascular wall from a nonerodible polymeric stentcoating in a range of doses (35-430 ug/5-18 mm coronary stent) producesa peak fifty to fifty-five percent reduction in neointimal hyperplasiaas set forth in Table 3 below. This reduction, which is maximal at abouttwenty-eight to thirty days, is typically not sustained in the range ofninety to one hundred eighty days in the porcine model as set forth inTable 4 below. TABLE 3.0 Animal Studies with Rapamycin-coated stents.Values are mean ± Standard Error of Mean Neointimal Area % Change FromStudy Duration Stent¹ Rapamycin N (mm²) Polyme Metal Porcine 98009 14days Metal 8 2.04 ± 0.17 1X + rapamycin 153 μg 8 1.66 ± 0.17* −42% −19%1X + TC300 + rapamycin 155 μg 8 1.51 ± 0.19* −47% −26% 99005 28 daysMetal 10 2.29 ± 0.21 9 3.91 ± 0.60** 1X + TC30 + rapamycin 130 μg 8 2.81± 0.34 +23% 1X + TC100 + rapamycin 120 μg 9 2.62 ± 0.21 +14% 99006 28days Metal 12 4.57 ± 0.46 EVA/BMA 3X 12 5.02 ± 0.62 +10% 1X + rapamycin125 μg 11 2.84 ± 0.31* ** −43% −38% 3X + rapamycin 430 μg 12 3.06 ±0.17* ** −39% −33% 3X + rapamycin 157 μg 12 2.77 ± 0.41* ** −45% −39%99011 28 days Metal 11 3.09 ± 0.27 11 4.52 ± 0.37 1X + rapamycin 189 μg14 3.05 ± 0.35  −1% 3X + rapamycin/dex 182/363 μg 14 2.72 ± 0.71 −12%99021 60 days Metal 12 2.14 ± 0.25 1X + rapamycin 181 μg 12 2.95 ± 0.38+38% 99034 28 days Metal 8 5.24 ± 0.58 1X + rapamycin 186 μg 8 2.47 ±0.33** −53% 3X + rapamycin/dex 185/369 μg 6 2.42 ± 0.64** −54% 20001 28days Metal 6 1.81 ± 0.09 1X + rapamycin 172 μg 5 1.66 ± 0.44  −8% 2000730 days Metal 9 2.94 ± 0.43 1XTC + rapamycin 155 μg 10 1.40 ± 0.11* −52%* Rabbit 99019 28 days Metal 8 1.20 ± 0.07 EVA/BMA 1X 10 1.26 ±0.16  +5% 1X + rapamycin 64 μg 9 0.92 ± 0.14 −27% −23% 1X + rapamycin196 μg 10 0.66 ± 0.12* ** −48% −45% 99020 28 days Metal 12 1.18 ± 0.10EVA/BMA 1X + rapamycin 197 μg 8 0.81 ± 0.16 −32%

[0044] TABLE 4.0 180 day Porcine Study with Rapamycin-coated stents.Values are mean ± Standard Error of Mean Neointimal Area % Change FromInflammation Study Duration Stent¹ Rapamycin N (mm²) Polyme Metal Score# 20007  3 days Metal 10 0.38 ± 0.06 1.05 ± 0.06 (ETP-2-002233-P) 1XTC +rapamycin 155 μg 10 0.29 ± 0.03 −24% 1.08 ± 0.04  30 days Metal 9 2.94 ±0.43 0.11 ± 0.08 1XTC + rapamycin 155 μg 10  1.40 ± 0.11*  −52%* 0.25 ±0.10  90 days Metal 10 3.45 ± 0.34 0.20 ± 0.08 1XTC + rapamycin 155 μg10 3.03 ± 0.29 −12% 0.80 ± 0.23 1X + rapamycin 171 μg 10 2.86 ± 0.35−17% 0.60 ± 0.23 180 days Metal 10 3.65 ± 0.39 0.65 ± 0.21 1XTC +rapamycin 155 μg 10 3.34 ± 0.31  −8% 1.50 ± 0.34 1X + rapamycin 171 μg10 3.87 ± 0.28  +6% 1.68 ± 0.37

[0045] The release of rapamycin into the vascular wall of a human from anonerodible polymeric stent coating provides superior results withrespect to the magnitude and duration of the reduction in neointimalhyperplasia within the stent as compared to the vascular walls ofanimals as set forth above.

[0046] Humans implanted with a rapamycin coated stent comprisingrapamycin in the same dose range as studied in animal models using thesame polymeric matrix, as described above, reveal a much more profoundreduction in neointimal hyperplasia than observed in animal models,based on the magnitude and duration of reduction in neointima. The humanclinical response to rapamycin reveals essentially total abolition ofneointimal hyperplasia inside the stent using both angiographic andintravascular ultrasound measurements. These results are sustained forat least one year as set forth in Table 5 below. TABLE 5.0 PatientsTreated (N = 45 patients) with a Rapamycin-coated Stent Sirolimus FIM95% Effectiveness Measures (N = 45 Patients, 45 Lesions) ConfidenceLimit Procedure Success (QCA) 100.0% (45/45) [92.1%, 100.0%]  4-monthIn-Stent Diameter Stenosis (%) Mean ± SD (N) 4.8% ± 6.1% (30) [2.6%,7.0%] Range (min, max) (−8.2%, 14.9%)  6-month In-Stent DiameterStenosis (%) Mean ± SD (N) 8.9% ± 7.6% (13) [4.8%, 13.0%] Range (min,max) (−2.9%, 20.4%) 12-month In-Stent Diameter Stenosis (%) Mean ± SD(N) 8.9% ± 6.1% (15) [5.8%, 12.0%] Range (min, max) (−3.0%, 22.0%) 4-month In-Stent Late Loss (mm) Mean ± SD (N) 0.00 ± 0.29 (30) [−0.10,0.10] Range (min, max) (−0.51, 0.45)  6-month In-Stent Late Loss (mm)Mean ± SD (N) 0.25 ± 0.27 (13) [0.10, 0.39] Range (min, max) (−0.51,0.91) 12-month In-Stent Late Loss (mm) Mean ± SD (N) 0.11 ± 0.36 (15)[−0.08, 0.29] Range (min, max) (−0.51, 0.82)  4-month Obstruction Volume(%) (IVUS) Mean ± SD (N) 10.48% ± 2.78% (28) [9.45%, 11.51%] Range (min,max) (4.60%, 16.35%)  6-month Obstruction Volume (%) (IVUS) Mean ± SD(N) 7.22% ± 4.60% (13) [4.72%, 9.72%], Range (min, max) (3.82%, 19.88%)12-month Obstruction Volume (%) (IVUS) Mean ± SD (N) 2.11% ± 5.28% (15)[0.00%, 4.78%], Range (min, max) (0.00%, 19.89%)  6-month Target LesionRevascularization (TLR) 0.0% (0/30) [0.0%, 9.5%] 12-month Target LesionRevascularization 0.0% (0/15) [0.0%, 18.1%] (TLR)

[0047] Rapamycin produces an unexpected benefit in humans when deliveredfrom a stent by causing a profound reduction in in-stent neointimalhyperplasia that is sustained for at least one year. The magnitude andduration of this benefit in humans is not predicted from animal modeldata. Rapamycin used in this context includes rapamycin and all analogs,derivatives and congeners that bind FKBP12 and possess the samepharmacologic properties as rapamycin.

[0048] These results may be due to a number of factors. For example, thegreater effectiveness of rapamycin in humans is due to greatersensitivity of its mechanism(s) of action toward the pathophysiology ofhuman vascular lesions compared to the pathophysiology of animal modelsof angioplasty. In addition, the combination of the dose applied to thestent and the polymer coating that controls the release of the drug isimportant in the effectiveness of the drug.

[0049] As stated above, rapamycin reduces vascular hyperplasia byantagonizing smooth muscle proliferation in response to mitogenicsignals that are released during angioplasty injury. Also, it is knownthat rapamycin prevents T-cell proliferation and differentiation whenadministered systemically. It has also been determined that rapamycinexerts a local inflammatory effect in the vessel wall when administeredfrom a stent in low doses for a sustained period of time (approximatelytwo to six weeks). The local anti-inflammatory benefit is profound andunexpected. In combination with the smooth muscle anti-proliferativeeffect, this dual mode of action of rapamycin may be responsible for itsexceptional efficacy.

[0050] Accordingly, rapamycin delivered from a local device platform,reduces neointimal hyperplasia by a combination of anti-inflammatory andsmooth muscle anti-proliferative effects. Rapamycin used in this contextmeans rapamycin and all analogs, derivatives and congeners that bindFKBP12 and possess the same pharmacologic properties as rapamycin. Localdevice platforms include stent coatings, stent sheaths, grafts and localdrug infusion catheters or porous balloons or any other suitable meansfor the in situ or local delivery of drugs, agents or compounds.

[0051] The anti-inflammatory effect of rapamycin is evident in data froman experiment, illustrated in Table 6, in which rapamycin delivered froma stent was compared with dexamethasone delivered from a stent.Dexamethasone, a potent steroidal anti-inflammatory agent, was used as areference standard. Although dexamethasone is able to reduceinflammation scores, rapamycin is far more effective than dexamethasonein reducing inflammation scores. In addition, rapamycin significantlyreduces neointimal hyperplasia, unlike dexamethasone. TABLE 6.0 GroupRapamycin Neointimal Area % Area Inflammation Rap N= (mm²) StenosisScore Uncoated 8 5.24 ± 1.65  54 ± 19  0.97 ± 1.00  Dexamethasone 8 4.31± 3.02  45 ± 31  0.39 ± 0.24  (Dex) Rapamycin 7 2.47 ± 0.94* 26 ± 10*0.13 ± 0.19* (Rap) Rap + Dex 6 2.42 ± 1.58* 26 ± 18* 0.17 ± 0.30*

[0052] Rapamycin has also been found to reduce cytokine levels invascular tissue when delivered from a stent. The data in FIG. 1illustrates that rapamycin is highly effective in reducing monocytechemotactic protein (MCP-1) levels in the vascular wall. MCP-1 is anexample of a proinflammatory/chemotactic cytokine that is elaboratedduring vessel injury. Reduction in MCP-1 illustrates the beneficialeffect of rapamycin in reducing the expression of proinflammatorymediators and contributing to the anti-inflammatory effect of rapamycindelivered locally from a stent. It is recognized that vascularinflammation in response to injury is a major contributor to thedevelopment of neointimal hyperplasia.

[0053] Since rapamycin may be shown to inhibit local inflammatory eventsin the vessel it is believed that this could explain the unexpectedsuperiority of rapamycin in inhibiting neointima.

[0054] As set forth above, rapamycin functions on a number of levels toproduce such desired effects as the prevention of T-cell proliferation,the inhibition of negative remodeling, the reduction of inflammation,and the prevention of smooth muscle cell proliferation. While the exactmechanisms of these functions are not completely known, the mechanismsthat have been identified may be expanded upon.

[0055] Studies with rapamycin suggest that the prevention of smoothmuscle cell proliferation by blockade of the cell cycle is a validstrategy for reducing neointimal hyperplasia. Dramatic and sustainedreductions in late lumen loss and neointimal plaque volume have beenobserved in patients receiving rapamycin delivered locally from a stent.The present invention expands upon the mechanism of rapamycin to includeadditional approaches to inhibit the cell cycle and reduce neointimalhyperplasia without producing toxicity.

[0056] The cell cycle is a tightly controlled biochemical cascade ofevents that regulate the process of cell replication. When cells arestimulated by appropriate growth factors, they move from G₀ (quiescence)to the G1 phase of the cell cycle. Selective inhibition of the cellcycle in the G1 phase, prior to DNA replication (S phase), may offertherapeutic advantages of cell preservation and viability whileretaining anti-proliferative efficacy when compared to therapeutics thatact later in the cell cycle i.e. at S, G2 or M phase.

[0057] Accordingly, the prevention of intimal hyperplasia in bloodvessels and other conduit vessels in the body may be achieved using cellcycle inhibitors that act selectively at the G1 phase of the cell cycle.These inhibitors of the G1 phase of the cell cycle may be smallmolecules, peptides, proteins, oligonucleotides or DNA sequences. Morespecifically, these drugs or agents include inhibitors of cyclindependent kinases (cdk's) involved with the progression of the cellcycle through the G1 phase, in particular cdk2 and cdk4.

[0058] Examples of drugs, agents or compounds that act selectively atthe G1 phase of the cell cycle include small molecules such asflavopiridol and its structural analogs that have been found to inhibitcell cycle in the late G1 phase by antagonism of cyclin dependentkinases. Therapeutic agents that elevate an endogenous kinase inhibitoryprotein^(kip) called P27, sometimes referred to as P27^(kip1), thatselectively inhibits cyclin dependent kinases may be utilized. Thisincludes small molecules, peptides and proteins that either block thedegradation of P27 or enhance the cellular production of P27, includinggene vectors that can transfact the gene to produce P27. Staurosporinand related small molecules that block the cell cycle by inhibitingprotein kinases may be utilized. Protein kinase inhibitors, includingthe class of tyrphostins that selectively inhibit protein kinases toantagonize signal transduction in smooth muscle in response to a broadrange of growth factors such as PDGF and FGF may also be utilized.

[0059] Any of the drugs, agents or compounds discussed above may beadministered either systemically, for example, orally, intravenously,intramuscularly, subcutaneously, nasally or intradermally, or locally,for example, stent coating, stent covering or local delivery catheter.In addition, the drugs or agents discussed above may be formulated forfast-release or slow release with the objective of maintaining the drugsor agents in contact with target tissues for a period ranging from threedays to eight weeks.

[0060] As set forth above, the complex of rapamycin and FKPB12 binds toand inhibits a phosphoinositide (PI)-3 kinase called the mammalianTarget of Rapamycin or TOR. An antagonist of the catalytic activity ofTOR, functioning as either an active site inhibitor or as an allostericmodulator, i.e. an indirect inhibitor that allosterically modulates,would mimic the actions of rapamycin but bypass the requirement forFKBP12. The potential advantages of a direct inhibitor of TOR includebetter tissue penetration and better physical/chemical stability. Inaddition, other potential advantages include greater selectivity andspecificity of action due to the specificity of an antagonist for one ofmultiple isoforms of TOR that may exist in different tissues, and apotentially different spectrum of downstream effects leading to greaterdrug efficacy and/or safety.

[0061] The inhibitor may be a small organic molecule (approximatemw<1000), which is either a synthetic or naturally derived product.Wortmanin may be an agent which inhibits the function of this class ofproteins. It may also be a peptide or an oligonucleotide sequence. Theinhibitor may be administered either sytemically (orally, intravenously,intramuscularly, subcutaneously, nasally, or intradermally) or locally(stent coating, stent covering, local drug delivery catheter). Forexample, the inhibitor may be released into the vascular wall of a humanfrom a nonerodible polymeric stent coating. In addition, the inhibitormay be formulated for fast-release or slow release with the objective ofmaintaining the rapamycin or other drug, agent or compound in contactwith target tissues for a period ranging from three days to eight weeks.

[0062] As stated previously, the implantation of a coronary stent inconjunction with balloon angioplasty is highly effective in treatingacute vessel closure and may reduce the risk of restenosis.Intravascular ultrasound studies (Mintz et al., 1996) suggest thatcoronary stenting effectively prevents vessel constriction and that mostof the late luminal loss after stent implantation is due to plaquegrowth, probably related to neointimal hyperplasia. The late luminalloss after coronary stenting is almost two times higher than thatobserved after conventional balloon angioplasty. Thus, inasmuch asstents prevent at least a portion of the restenosis process, the use ofdrugs, agents or compounds which prevent inflammation and proliferation,or prevent proliferation by multiple mechanisms, combined with a stentmay provide the most efficacious treatment for post-angioplastyrestenosis.

[0063] The local delivery of drugs, agents or compounds from a stent hasthe following advantages; namely, the prevention of vessel recoil andremodeling through the scaffolding action of the stent and the drugs,agents or compounds and the prevention of multiple components ofneointimal hyperplasia. This local administration of drugs, agents orcompounds to stented coronary arteries may also have additionaltherapeutic benefit. For example, higher tissue concentrations would beachievable than that which would occur with systemic administration,reduced systemic toxicity, and single treatment and ease ofadministration. An additional benefit of drug therapy may be to reducethe dose of the therapeutic compounds, thereby limiting their toxicity,while still achieving a reduction in restenosis.

[0064] There are a multiplicity of different stents that may be utilizedfollowing percutaneous transluminal coronary angioplasty. Although anynumber of stents may be utilized in accordance with the presentinvention, for simplicity, one particular stent will be described inexemplary embodiments of the present invention. The skilled artisan willrecognize that any number of stents may be utilized in connection withthe present invention.

[0065] A stent is commonly used as a tubular structure left inside thelumen of a duct to relieve an obstruction. Commonly, stents are insertedinto the lumen in a non-expanded form and are then expandedautonomously, or with the aid of a second device in situ. A typicalmethod of expansion occurs through the use of a catheter-mountedangioplasty balloon which is inflated within the stenosed vessel or bodypassageway in order to shear and disrupt the obstructions associatedwith the wall components of the vessel and to obtain an enlarged lumen.As set forth below, self-expanding stents may also be utilized.

[0066]FIG. 2 illustrates an exemplary stent 100 which may be utilized inaccordance with an exemplary embodiment of the present invention. Theexpandable cylindrical stent 100 comprises a fenestrated structure forplacement in a blood vessel, duct or lumen to hold the vessel, duct orlumen open, more particularly for protecting a segment of artery fromrestenosis after angioplasty. The stent 100 may be expandedcircumferentially and maintained in an expanded configuration, that iscircumferentially or radially rigid. The stent 100 is axially flexibleand when flexed at a band, the stent 100 avoids anyexternally-protruding component parts.

[0067] The stent 100 generally comprises first and second ends with anintermediate section therebetween. The stent 100 has a longitudinal axisand comprises a plurality of longitudinally disposed bands 102, whereineach band 102 defines a generally continuous wave along a line segmentparallel to the longitudinal axis. A plurality of circumferentiallyarranged links 104 maintain the bands 102 in a substantially tubularstructure. Essentially, each longitudinally disposed band 102 isconnected at a plurality of periodic locations, by a shortcircumferentially arranged link 104 to an adjacent band 102. The waveassociated with each of the bands 102 has approximately the samefundamental spatial frequency in the intermediate section, and the bands102 are so disposed that the wave associated with them are generallyaligned so as to be generally in phase with one another. As illustratedin the figure, each longitudinally arranged band 102 undulates throughapproximately two cycles before there is a link to an adjacent band.

[0068] The stent 100 may be fabricated utilizing any number of methods.For example, the stent 100 may be fabricated from a hollow or formedstainless steel tube that may be machined using lasers, electricdischarge milling, chemical etching or other means. The stent 100 isinserted into the body and placed at the desired site in an unexpandedform. In one embodiment, expansion may be effected in a blood vessel bya balloon catheter, where the final diameter of the stent 100 is afunction of the diameter of the balloon catheter used.

[0069] It should be appreciated that a stent 100 in accordance with thepresent invention may be embodied in a shape-memory material, including,for example, an appropriate alloy of nickel and titanium. In thisembodiment, after the stent 100 has been formed it may be compressed soas to occupy a space sufficiently small as to permit its insertion in ablood vessel or other tissue by insertion means, wherein the insertionmeans include a suitable catheter, or flexible rod. On emerging from thecatheter, the stent 100 may be configured to expand into the desiredconfiguration where the expansion is automatic or triggered by a changein pressure, temperature or electrical stimulation.

[0070]FIG. 3 illustrates an exemplary embodiment of the presentinvention utilizing the stent 100 illustrated in FIG. 2. As illustrated,the stent 100 may be modified to comprise a reservoir 106. Each of thereservoirs may be opened or closed as desired. These reservoirs 106 maybe specifically designed to hold the drug, agent, compound orcombinations thereof to be delivered. Regardless of the design of thestent 100, it is preferable to have the drug, agent, compound orcombinations thereof dosage applied with enough specificity and asufficient concentration to provide an effective dosage in the lesionarea. In this regard, the reservoir size in the bands 102 is preferablysized to adequately apply the drug/drug combination dosage at thedesired location and in the desired amount.

[0071] In an alternate exemplary embodiment, the entire inner and outersurface of the stent 100 may be coated with various drug and drugcombinations in therapeutic dosage amounts. A detailed description ofexemplary coating techniques is described below.

[0072] Rapamycin or any of the drugs, agents or compounds describedabove may be incorporated into or affixed to the stent in a number ofways and utilizing any number of biocompatible materials. In theexemplary embodiment, the rapamycin is directly incorporated into apolymeric matrix and sprayed onto the outer surface of the stent. Therapamycin elutes from the polymeric matrix over time and enters thesurrounding tissue. The rapamycin preferably remains on the stent for atleast three days up to approximately six months and more preferablybetween seven and thirty days.

[0073] Any number of non-erodible polymers may be utilized inconjunction with rapamycin. In the exemplary embodiment, the polymericmatrix comprises two layers. The base layer comprises a solution ofethylene-co-vinylacetate and polybutylmethacrylate. The rapamycin isincorporated into this layer. The outer layer comprises onlypolybutylmethacrylate and acts as a diffusion barrier to prevent therapamycin from eluting too quickly and entering the surrounding tissues.The thickness of the outer layer or top coat determines the rate atwhich the rapamycin elutes from the matrix. Essentially, the rapamycinelutes from the matrix by diffusion through the polymer molecules.Polymers tend to move, thereby allowing solids, liquids and gases toescape therefrom. The total thickness of the polymeric matrix is in therange from about 1 micron to about 20 microns or greater. In a preferredexemplary embodiment, the base layer, including the polymer and drug,has a thickness in the range from about 8 microns to about 12 micronsand the outer layer has a thickness in the range from about 1 micron toabout 2 microns.

[0074] The ethylene-co-vinylacetate, polybutylmethacrylate and rapamycinsolution may be incorporated into or onto the stent in a number of ways.For example, the solution may be sprayed onto the stent or the stent maybe dipped into the solution. In a preferred embodiment, the solution issprayed onto the stent and then allowed to dry. In another exemplaryembodiment, the solution may be electrically charged to one polarity andthe stent electrically changed to the opposite polarity. In this manner,the solution and stent will be attracted to one another. In using thistype of spraying process, waste may be reduced and more control over thethickness of the coat may be achieved.

[0075] Since rapamycin works by entering the surrounding tissue, it ispreferably only affixed to the surface of the stent making contact withone tissue. Typically, only the outer surface of the stent makes contactwith the tissue. Accordingly, in a preferred embodiment, only the outersurface of the stent is coated with rapamycin. For other drugs, agentsor compounds, the entire stent may be coated.

[0076] It is important to note that different polymers may be utilizedfor different stents. For example, in the above-described embodiment,ethylene-co-vinylacetate and polybutylmethacrylate are utilized to formthe polymeric matrix. This matrix works well with stainless steelstents. Other polymers may be utilized more effectively with stentsformed from other materials, including materials that exhibitsuperelastic properties such as alloys of nickel and titanium.

[0077] Although shown and described is what is believed to be the mostpractical and preferred embodiments, it is apparent that departures fromspecific designs and methods described and shown will suggest themselvesto those skilled in the art and may be used without departing from thespirit and scope of the invention. The present invention is notrestricted to the particular constructions described and illustrated,but should be constructed to cohere with all modifications that may fallwithin the scope of the appended claims.

What is claimed is:
 1. A method for preventing constrictive vascularremodeling comprising a controlled delivery, by release from a stent, ofa compound having anti-proliferative and anti-inflammatory properties intherapeutic dosage amounts in the range from about thirty-fivemicrograms per fifteen to eighteen millimeters of stent to about fourhundred thirty micrograms per fifteen to eighteen millimeters of stent,the compound substantially reducing in-lesion lumen loss both proximateand distal to the stent, the compound being incorporated in a polymericmatrix comprising first and second layers wherein the compound issubstantially in the first layer and the second layer acts as adiffusion barrier for the controlled release of the compound, and havinga thickness in the range from about one micron to about 20 microns withthe first layer having a thickness in the range from about 8 microns toabout 12 microns and the second layer having a thickness in the rangefrom about 1 micron to about 2 microns.
 2. The method for preventingconstrictive remodeling according to claim 1, further includes utilizingthe compound to block a proliferation of fibroblasts in a vascular wallin response to injury, thereby reducing a formation of vascular scartissue.
 3. The method for preventing constrictive remodeling accordingto claim 2, wherein the compound comprises rapamycin.
 4. The method forpreventing constrictive remodeling according to claim 2, wherein thecompound comprises analogs and congeners that bind a high-affinitycytosolic protein, FKBP12, and possesses pharmacologic propertiesequivalent to rapamycin.
 5. The method for preventing constrictiveremodeling according to claim 1, further includes utilizing the compoundto affect a translation of certain proteins involved in a collagenformation or metabolism.
 6. The method for preventing constrictiveremodeling according to claim 5, wherein the compound comprisesrapamycin.
 7. The method for preventing constrictive remodelingaccording to claim 5, wherein the compound comprises analogs andcongeners that bind a high-affinity cytosolic protein, FKBP12, andpossesses pharmacologic properties equivalent to rapamycin.
 8. A drugdelivery device for treating constrictive vascular remodelingcomprising: a stent; and a therapeutic dosage, in the range from aboutthirty-five micrograms per fifteen to eighteen millimeters of stent toabout four hundred thirty micrograms per fifteen to eighteen millimetersof stent, of an agent having anti-proliferative and anti-inflammatoryproperties releasably affixed to the stent for treatment of constrictivevascular remodeling, the agent substantially reducing in-lesion lumenloss both proximal and distal to the intraluminal medical device, theagent being incorporated in a polymeric matrix comprising first andsecond layers, the agent is substantially in the first layer and thesecond layer acts as a diffusion barrier for the controlled release ofthe agent, the polymeric matrix having a thickness in the range fromabout one micron to about 20 microns.
 9. The drug delivery deviceaccording to claim 8, wherein the agent blocks a proliferation offibroblasts in a vascular wall in response to injury, thereby reducing aformation of vascular scar tissue.
 10. The drug delivery deviceaccording to claim 9, wherein the agent comprises rapamycin.
 11. Thedrug delivery device according to claim 9, wherein the agent comprisesanalogs and congeners that bind a high-affinity cytosolic protein,FKBP12, and possesses pharmacologic properties equivalent to rapamycin.12. The drug delivery device according to claim 8, wherein the agentaffects the translation of certain proteins involved in collagenformation or metabolism.
 13. The drug delivery device according to claim12, wherein the agent comprises rapamycin.
 14. The drug delivery deviceaccording to claim 12, wherein the agent comprises analogs and congenersthat bind a high-affinity cytosolic protein, FKBP12, and possessespharmacologic properties equivalent to rapamycin.